Primary cutaneous follicle center lymphoma

INTRODUCTION — 

Primary cutaneous B cell lymphoma (PCBCL) refers to cases of B cell lymphoma that present in the skin with no evidence of extracutaneous disease at diagnosis and after completing an initial staging evaluation. There are three main categories of PCBCL, which have different clinical presentations, pathologic features, prognosis, and management:

●Primary cutaneous follicle center lymphoma (PCFCL)

●Primary cutaneous large B cell lymphoma, leg type

●Primary cutaneous marginal zone lymphoma (also called primary cutaneous marginal zone lymphoproliferative disorder)

PCFCL is the most common type of PCBCL. It typically presents with firm solitary or grouped skin lesions on the head, neck, or trunk. PCFCL was previously called primary cutaneous follicle center cell lymphoma.

This topic review discusses clinical presentation, diagnosis, and management of PCFCL.

Other primary cutaneous lymphomas are discussed separately.

●(See "Primary cutaneous marginal zone lymphoma".)

●(See "Primary cutaneous diffuse large B cell lymphoma, leg type".)

●(See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".)

●(See "Primary cutaneous T cell lymphomas, rare subtypes".)

EPIDEMIOLOGY — 

PCFCL is the most common category of primary cutaneous B cell lymphoma (PCBCL).

Approximately one-quarter of all cases of non-Hodgkin lymphoma present at an extranodal site without systemic involvement. The skin is the second most common primary extranodal site, second in frequency only to the gastrointestinal tract.

The overall incidence of primary cutaneous lymphomas in Western countries is estimated to be 0.5 to 1 case per 100,000 people annually. Of these, approximately 20 to 25 percent represent PCBCL [1-3]. The incidence varies geographically, with lower rates in Japan and Korea [4,5].

PCFCL accounts for approximately one-half of cases of PCBCL [1]. Although PCFCL can occur in patients as young as 20 years, it is primarily a disease of middle-aged to older patients [6,7]. The median age at onset is 51 years, and the male:female ratio is approximately 1.5:1 [8-10]. The vast majority of cases occur in non-Hispanic white individuals [9].

PATHOGENESIS — 

PCFCL is thought to arise from mature germinal center B cells, but there are no clearly defined risk factors and no identifiable hereditary tendency.

Pathogenetic links between primary cutaneous B cell lymphomas (PCBCLs) and Borrelia burgdorferi infection have been established in Europe, but North American and Asian case series have thus far failed to demonstrate a similar relationship. B. burgdorferi infection is seen more commonly in primary cutaneous marginal zone lymphoma, and only rarely in PCFCL. Although case reports have suggested a link between PCBCL and viral infection (eg, Epstein-Barr virus, human immunodeficiency virus [HIV], hepatitis C virus), no definitive evidence exists. This is discussed in more detail separately. (See "Primary cutaneous marginal zone lymphoma", section on 'Pathogenesis'.)

B cell receptor genes in PCFCL can acquire N-linked glycosylation motifs; this observation is similar to nodal follicular lymphomas, but it contrasts with primary cutaneous diffuse large B cell lymphoma, leg type [11]. These observations suggest that lectins from commensal skin bacteria may contribute to the pathogenesis of PCFCL.

CLINICAL PRESENTATION — 

PCFCL typically presents with firm, solitary or grouped skin lesions on the head, neck, or trunk.

Lesions of PCFCL are typically firm, painless, nonpruritic, erythematous papules, plaques, or tumors with a predilection for the head, neck, and trunk (picture 1 and picture 2) [12-14]. Approximately 5 percent of patients have lesions on the legs, while 15 percent present with multifocal skin lesions [8,12].

The lesions of PCFCL are generally smooth and do not typically ulcerate; superficial scaling may be present [15,16]. Surrounding annular erythema, which may be papular, has been described [17]. Most cases consist of a solitary lesion <5 cm [14]. Disseminated lesions are rare, although cases with a dermatomal distribution have been reported [18]. A multicenter retrospective study described the presence of small papular skin lesions located at a distance from the main affected area in 3 of 24 patients with a PCFCL; interestingly, these distant lesions resolved spontaneously in all three patients [19].

The lesions tend to progress slowly and may be present for >20 years before a diagnosis is established; a latent phase of several years is the norm [20]. Systemic "B" symptoms (ie, fever, weight loss, night sweats) were reported in only 2 of 84 cases in one series [21].

EVALUATION — 

The patient is evaluated with a thorough history and physical examination, laboratory testing, and usually with imaging at baseline. A diagnostic skin biopsy is obtained. The staging studies are used to exclude other categories of lymphomas.

Clinical and laboratory

●Clinical – History should include the duration of skin lesions and presence of constitutional symptoms (ie, unexplained fevers, drenching sweats, weight loss). Physical examination includes a complete skin examination for skin nodules and an evaluation for lymphadenopathy and/or organomegaly.

The presence of "B" symptoms (eg, unexplained fever, drenching sweats, weight loss) should raise suspicion of a systemic lymphoma.

●Laboratory studies

•Hematology – Complete blood count (CBC) with differential count.

•Serum chemistries – Comprehensive metabolic panel, including lactate dehydrogenase.

•Infectious – Testing for hepatitis B, hepatitis C, and HIV.

•Other

-Flow cytometry of peripheral blood should be performed if there is lymphocytosis on CBC.

-Bone marrow examination is useful for evaluating unexplained cytopenias, to clarify equivocal results from positron emission tomography (PET)/computed tomography (CT), and other circumstances where systemic follicular lymphoma is suspected. (See 'Staging' below.)

-Pregnancy test, if clinically applicable.

Imaging — PET/CT is obtained to confirm that the disease is limited to the skin, thereby excluding other categories of lymphoma.

Contrast-enhanced CT of the chest/abdomen/pelvis may be performed as an alternative, if clinically indicated. The neck should be included in case of head and neck lesions and if there is palpable adenopathy.

Skin biopsy — An adequate biopsy specimen is required for diagnosis. Excisional biopsies are preferred, but if a punch biopsy is taken, the diameter should be ≥4 millimeters. Shave biopsies are inadequate for diagnosis.

The skin biopsy specimen is evaluated for:

●Microscopy – Morphology and growth pattern.

●Immunohistochemistry – Immunohistochemistry (IHC) should be performed on paraffin sections. Flow cytometry is not routinely used because it is difficult to make single-cell suspensions with this tumor type.

IHC studies should include B cell antigens (CD19, CD20, CD79a), CD5, BCL2, BCL6, MUM1/IRF4, Ki-67, and immunoglobulin (Ig) kappa and lambda light chains.

IHC can be helpful for distinguishing PCFCL from other conditions. Polarization of Ki-67-positive cells is seen in reactive, but not in neoplastic, germinal centers. If PCFCL must be distinguished from primary cutaneous diffuse large B cell lymphoma (PCDLBCL), leg type (eg, because of ambiguous morphology), IHC for FOXP1, IgM, IgD, CD21, and Ki-67 can be helpful; CD21 staining can reveal remnants of follicular dendritic cell networks that are not found in PCDLBCL, leg type, and Ki-67 staining reveals a lower proliferative index with PCFCL.

●Cytogenetics/molecular analysis – Chromosome banding and fluorescence in situ hybridization (FISH) are not required for diagnosis.

If FISH is performed, it should include evaluation for BCL2 and BCL6 translocations.

Immunoglobulin heavy chain rearrangement can be used to demonstrate the clonality of the lymphoid cells.

Pathologic findings are described below. (See 'Pathologic features' below.)

PATHOLOGIC FEATURES

Morphology — Skin biopsy demonstrates dermal and subcutaneous infiltration, which almost always spares the epidermis [22].

The area of infiltration can be perivascular, periadnexal, or diffuse. Growth can be in a follicular, follicular and diffuse, or diffuse pattern. When a follicular pattern is present, the follicles are ill-defined and they have a decreased mantle zone, lack tingible body macrophages, and show a monotonous proliferation of BCL6-positive follicle center cells. Interfollicular areas contain a mixed cellular population of small and large lymphocytes and histiocytes. In more advanced PCFCL, the follicles may be less pronounced or absent.

The malignant lesions are composed of predominantly medium-sized and large centrocytes (large cleaved follicle center cells) and variable proportions of centroblasts (large follicle center cells with prominent nucleoli) (picture 3) [23]. In some cases, the centrocytes are intermixed with multilobated cells and spindle cells (picture 4).

Unlike nodal follicular lymphoma, PCFCL is not routinely graded because there is no correlation between grade and prognosis.

Immunophenotype — Virtually all cases express pan-B cell antigens (CD19, CD20, CD79a), and they are always CD5 negative [23].

Most cases express BCL6 but do not express BCL2, and CD10 expression is variable [19,24]. Staining for kappa and lambda light chains may reveal monotypic surface immunoglobulin (Ig) or the cells may lack surface Ig; cytoplasmic Ig is usually negative.

Markers of proliferation are variable, with one report demonstrating 9 of 24 cases with 60 to 90 percent Ki-67-positive cells [19]. Staining with CD21 or CD35 usually reveals focal remnants of follicular dendritic cell meshwork [22]. The plasma cell marker MUM1/IRF4 is negative [25].

Genetics — No single cytogenetic change is typical or diagnostic of PCFCL.

The t(14;18) translocation or BCL2 gene rearrangement has been reported in 0 to 40 percent of cases of PCFCL [7,19,26-28]. This differs from nodal follicular lymphomas, in which these findings are present in most cases.

Deletion of chromosome 14q32.33 has been reported [29]. A subset of PCFCL patients may show 1p36 deletions and/or somatic mutations of the TNFRSF14 gene [30-32]. By contrast to primary cutaneous B cell lymphoma, leg type, deletions of a small region on chromosome 9p21.3 containing the CDKN2A and CDKN2B gene loci and MYD88 mutations are rare or absent in PCFCL [29,33].

Mutations in CREBBP and KTM2D are less common in PCFCL than in nodal follicular lymphomas [31,32]. The gene expression profile of PCFCL is like that of germinal center-like large B cell lymphomas, and it often has amplifications of the REL gene [25,29].

STAGING — 

Staging of PCFCL is based on clinical evaluation, laboratory studies, and imaging, including positron emission tomography (PET)/CT.

Patients are staged using the EORTC (European Organisation for Research and Treatment of Cancer)/ISCL (International Society for Cutaneous Lymphomas) TNM (tumor, node, metastases) staging system for primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome (table 1) [34].

Bone marrow examination is not required but can be helpful in certain circumstances. The findings can evaluate unexplained cytopenias, clarify equivocal results of marrow involvement from PET/CT, and investigate suspected systemic lymphoma in patients with t(14;18) rearrangement. Some clinicians perform bone marrow examination in all patients.

The presence of "B" symptoms, abnormal blood counts, or elevated lactate dehydrogenase should raise suspicion of a systemic lymphoma.

Details of the staging evaluation are discussed above. (See 'Evaluation' above.)

DIAGNOSIS — 

PCFCL should be suspected in individuals with solitary or grouped firm skin lesions on the head, neck, trunk, or other sites.

Diagnosis is based on a biopsy of involved skin that demonstrates characteristic morphology and immunophenotype in a patient with no evidence of systemic lymphoma after staging studies are completed.

Diagnosis of PCFCL is based on (table 2):

●Pathology [22]:

•Epidermis-sparing B cell infiltrate comprising centrocytes and centroblasts with a follicular or diffuse pattern.

•B cell lineage confirmed by expression of CD20 or CD79a and absence of CD3.

•Clonality demonstrated by immunohistochemistry or flow cytometry for immunoglobulin (Ig) light chain expression on paraffin sections or frozen sections, or by clonal Ig gene rearrangements.

●Staging studies confirm that involvement is limited to the skin.

The World Health Organization and the International Consensus Classification apply the same diagnostic criteria and labeling for PCFCL [1,35,36].

DIFFERENTIAL DIAGNOSIS — 

The firm, erythematous, painless, nonpruritic papules, plaques, or tumors of PCFCL can mimic arthropod bites, cutaneous lymphoid hyperplasia, and other cutaneous lymphomas. These conditions are distinguished by morphologic evaluation, immunohistochemical stains, and exclusion of extracutaneous involvement.

Reactive infiltrate — PCFCL must be distinguished from a reactive lymphoid infiltrate.

Follicular hyperplasia due to inflammation (eg, B. burgdorferi infection, tick bites) can mimic PCFCL. Unlike the follicles seen in cutaneous follicular hyperplasia, the follicles in PCFCL are ill-defined, have a decreased mantle zone, lack tingible body macrophages, and show a monotonous proliferation of BCL6-positive follicle center cells in a network of CD21-positive or CD35-positive follicular dendritic cells.

Inflammatory infiltrates have polyclonal surface immunoglobulin (Ig) expression, while PCFCL only rarely expresses Ig. Ki-67 staining to determine the proliferative fraction also helps to distinguish neoplastic and reactive follicles. The Ki-67-positive fraction is lower in PCFCL with a follicular growth pattern than in reactive follicles, but the proliferative fraction is generally >75 percent in PCFCL with a diffuse growth pattern. (See "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma", section on 'Reactive follicular hyperplasia'.)

Other cutaneous lymphomas — PCFCL must be distinguished from other cutaneous lymphomas.

Primary cutaneous diffuse large B cell lymphoma, leg type — Primary cutaneous diffuse large B cell lymphoma (PCDLBCL), leg type is far more aggressive and requires different treatment than PCFCL.

Despite its name, PCDLBCL, leg type can occur at sites other than the legs. These lesions have a diffuse pattern or a monotonous proliferation of centroblasts and/or immunoblasts on biopsy. By contrast to PCFCL, PCDLBCL, leg type strongly expresses BCL2, MUM1/IRF4, FOXP1, and IgM. A subset of patients with PCDLBCL, leg type have mutations in MYD88 [33], which is not seen in PCFCL. (See "Primary cutaneous diffuse large B cell lymphoma, leg type".)

Primary cutaneous marginal zone lymphoma — Primary cutaneous marginal zone lymphoma (PCMZL; in the World Health Organization 5^th edition [35]) is called primary cutaneous marginal zone lymphoproliferative disorder in the International Consensus Classification (ICC) [36] because of its indolent disease course. PCMZL is distinguished from PCFCL based on differences in clinical presentation and pathologic findings.

The red to violaceous papules, plaques, or nodules of PCMZL are localized preferentially on the trunk or upper extremities, and multifocal skin lesions are common.

The neoplastic cells of PCMZL have a BCL6-negative, BCL2-positive, and CD10-negative phenotype. Moreover, monotypic cytoplasmic Ig light chain expression by the lymphoplasmacytoid and plasma cells (typically located at the periphery of the nodular infiltrates and subepidermally) is a hallmark of PCMZL but is rarely observed in PCFCL. By contrast, PCFCL is characterized by a diffuse infiltrate of large cleaved cells (large centrocytes) with a BCL6-positive, BCL2-negative immunotype, with variable expression of CD10.

Morphologically, it may be difficult to distinguish between PCFCL with a (partly) follicular growth pattern and PCMZL with reactive follicular structures. In such cases, the differential expression of BCL6, BCL2, and CD10 is important to establish the correct diagnosis. Colonization of follicular structures by neoplastic marginal zone cells, which is often observed in extranodal marginal zone lymphomas arising at other sites, is rarely seen in PCMZL. (See "Primary cutaneous marginal zone lymphoma".)

Cutaneous T cell lymphoma — Cutaneous T cell lymphomas can be distinguished from PCFCL through their expression of T cell markers such as CD2, CD3, and CD5. In addition, cutaneous T cell lymphomas can be identified by T cell receptor (TCR) gene rearrangement studies, as discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides", section on 'Diagnosis'.)

Systemic lymphoma — Non-Hodgkin lymphoma (NHL) may involve the skin either as a primary entity or as a result of cutaneous spread from systemic disease. An estimated 6 to 10 percent of patients with systemic B cell NHL will develop cutaneous disease at some point in their illness [37].

PCFCL is distinguished from systemic lymphomas by the absence of extracutaneous involvement after a thorough staging evaluation. (See 'Staging' above.)

Follicular lymphoma — Biopsy specimens from follicular lymphoma (FL) can resemble those of PCFCL by morphology and immunophenotype. Characteristically, the tumor cells of FL express monotypic Ig light chain, CD20, CD10, and BCL6, and they are negative for CD5 and CD23. More than 85 percent of FL tumors express BCL2 and show the t(14;18) rearrangement.

By contrast, PCFCL only rarely expresses Ig and most cases are BCL2 negative. CD10 expression is variable. Strong expression of BCL2, BCL6, and CD10 should raise the suspicion of systemic FL with skin involvement. (See "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma".)

Evidence of extracutaneous involvement from staging studies excludes the diagnosis of PCFCL.

Intravascular lymphoma — Intravascular large B cell lymphoma is a rare NHL variant that typically presents as multiple, erythematous tender nodules, tumors, or telangiectasias in older patients. Isolated involvement of the skin does occur, but the disease more frequently affects multiple organ systems, including the central nervous system, kidneys, and adrenals, producing a wide variety of symptoms, ranging from generalized confusion or dementia to focal motor and sensory deficits. This condition is discussed in more detail separately. (See "Intravascular large B cell lymphoma".)

TREATMENT — 

Management of PCFCL is informed by symptoms and the number and distribution of cutaneous lesions symptoms.

The lesions of PCFCL are generally indolent, and management should aim to minimize treatment-related adverse effects (AEs). If untreated, PCFCL lesions typically increase in size gradually over years and only disseminate to extracutaneous sites in approximately 10 percent of patients [8,12,14].

PCFCL is rare, and treatment suggestions are primarily based on retrospective reviews and anecdotal reports.

Our approach is consistent with treatment recommendations of ISCL (the International Society for Cutaneous Lymphomas), ILROG (the International Lymphoma Radiation Oncology Group), and NCCN (the National Comprehensive Cancer Network) [38-41].

Solitary or localized lesions — For a cosmetically bothersome or symptomatic solitary lesion(s) that can be contained in one radiation field, we suggest radiation therapy (RT), rather than observation, surgical excision, or systemic therapy (algorithm 1), based on the efficacy, low morbidity, and low relapse rate with RT.

For patients who decline RT, topical or intralesional steroids, observation, or surgical excision are acceptable. Topical medium- or high-potency corticosteroids, or intralesional steroids can be used for symptomatic relief in patients who seek to avoid RT.

The preferred RT dose is 20 to 24 gray (Gy), with a ≥1 to 1.5 cm margin of uninvolved skin [40,41]. AEs are generally mild, but they vary with the site of involvement. Some patients may instead favor a very low-dose RT (VLDRT) for symptom relief [42].

Asymptomatic lesions that are not cosmetically bothersome can be treated with topical or intralesional steroids or observed for progression (algorithm 1).

Treatment outcomes are primarily from retrospective studies and case reports. The largest review included data from 713 patients with PCFCL [38].

●RT – Treatment of 460 patients with 20 to 54 Gy RT reported a 99 percent complete response (CR) rate and a 30 to 76 percent rate of relapse [38]. Treatment using smaller margins of healthy-appearing skin reported more in-field and marginal recurrences than those with larger margins [14].

VLDRT (2 x 2 Gy) can also be effective [43]. A retrospective study of 29 patients treated with VLDRT reported 90 percent response rate (including 68 percent complete response [CR]) and only 9 percent local progression for potentially curable, localized disease; however, outcomes were less favorable with lesions ≥6 cm [42].

●Surgical excision – Of 93 patients treated with surgical excision, 98 percent obtained a CR, but skin relapse was seen in 40 percent [38].

●Rituximab – Intralesional or systemic rituximab was associated with 80 to 90 percent CR in small numbers of patients [38,44-46]. Relapses in the skin are seen in most patients, with a median duration of response of approximately 40 months [46]. Intralesional rituximab in 35 patients with PCFCL or primary cutaneous marginal zone lymphoma was associated with a 71 percent CR, an eight-week median time to CR, and approximately two years median disease-free survival [47].

●Multiagent chemotherapy – Treatment of 104 patients with multiagent chemotherapy reported an 85 percent CR and relapses in 48 percent [38]. Most patients had large tumor burdens and treatment was primarily with CHOP-like regimens (cyclophosphamide, doxorubicin, vincristine, prednisone). There are few reports of the addition of rituximab to chemotherapy (eg, R-CHOP), and results have been mixed.

●Combined modality therapy – Multiagent chemotherapy followed by involved site RT reported a CR in all seven patients, with a relapse in one [38].

●Other agents – Case reports have described clinical responses to intralesional interferon alfa, topical class 1 corticosteroids (eg, clobetasol), topical nitrogen mustard, intralesional steroids, and cryotherapy [39].

Multiple sites or scattered lesions — For lesions that do not fit in one RT field, we suggest RT to symptomatic lesions (algorithm 1), rather than multiple surgeries, rituximab, or multiagent chemotherapy.

We generally limit RT to ≤3 sites of disease, but if additional symptomatic skin lesions develop, lower-dose RT (eg, 2 Gy x 2) often suffice [43]. Topical medium- or high-potency corticosteroids or intralesional steroids can also be used for symptomatic lesions.

Extensive or diffuse disease — For extensive or diffuse symptomatic disease, we suggest single-agent rituximab rather than observation, RT, or multiagent chemotherapy (algorithm 1) to provide symptomatic relief without excessive toxicity.

We use rituximab if there are multiple lesions on disparate areas of the body that are symptomatic and not responding to skin-directed therapy. We reserve combination chemotherapy for the rare cases with extremely extensive, symptomatic disease or for those who fail to respond to initial rituximab.

With this approach, systemic spread and disease-related deaths are uncommon, occurring in roughly 10 and 5 percent of patients, respectively, over a 10-year period [19,48,49].

FOLLOW-UP — 

Following the completion of therapy, patients are seen at periodic intervals to monitor for treatment complications and possible relapse.

For asymptomatic patients with a complete response, we examine the patient every three months for the first two years. Laboratory studies are not needed, and imaging should be avoided unless clinically warranted. The frequency of visits can then decrease, as guided by the concerns of the patient and clinician.

Imaging should be limited, particularly in younger individuals, given concerns about radiation exposure and the risk for second malignancies. (See "Radiation-related risks of imaging".)

Recurrences are almost always detected by clinical examination. In a retrospective analysis that included 20 patients with PCFCL followed for a median of 66 months, there were 23 episodes of recurrence, all of which were identified by physical examination [50]. Neither blood examinations nor imaging procedures established recurrence or progression in any patient.

RELAPSE — 

Approximately one-third of patients initially treated with radiation therapy (RT) relapse.

Most relapses after RT are confined to the skin. For cutaneous lesions that appear outside of the prior RT field, most patients respond to RT. For relapse within a prior RT field, surgical excision or single-agent rituximab may be used. Multiagent chemotherapy is rarely necessary. (See 'Treatment' above.)

The rare patient who develops extracutaneous disease may be managed as systemic follicular lymphoma, as discussed separately. (See "Initial treatment of stage II to IV follicular lymphoma".)

PROGNOSIS — 

Patients with PCFCL have an excellent prognosis and most experience an indolent clinical course. If untreated, lesions typically gradually increase in size over the years, while dissemination to extracutaneous sites is uncommon.

According to retrospective studies, five-year overall survival is approximately 95 percent [7,8,12,26,48,51]. Up to one-third of patients relapse after initial treatment with radiation therapy (RT) [14,38]. Approximately 10 percent of patients developed extracutaneous disease in two large studies [8,12].

PCFCL presenting with skin lesions on the leg are reported to have a more unfavorable prognosis [12,52,53]. The growth pattern (follicular, follicular and diffuse, or diffuse), number of blast cells, extent of skin lesions (solitary, regional, or multifocal), presence of t(14;18), or BCL2 expression have not been associated with survival outcomes.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary cutaneous lymphoma".)

SUMMARY AND RECOMMENDATIONS

●Description – Primary cutaneous B cell lymphoma refers to cases of B cell lymphoma that present in the skin with no evidence of extracutaneous disease after completing an initial staging evaluation.

●Epidemiology – Primary cutaneous follicle center lymphoma (PCFCL) is the most common category of primary cutaneous B cell lymphoma. PCFCL is primarily a disease of middle-aged to older patients, with a slight male predominance. (See 'Epidemiology' above.)

●Presentation – Patients typically present with firm, erythematous, painless, nonpruritic papules, nodules, or plaques with a predilection for the head, neck, and trunk. Lesions are generally smooth and do not typically ulcerate. Disseminated lesions are rare. (See 'Clinical presentation' above.)

●Evaluation – Clinical evaluation, diagnostic skin biopsy, and staging studies are performed. (See 'Evaluation' above.)

●Pathology – Skin biopsy demonstrates dermal and subcutaneous infiltration, which almost always spares the epidermis.

•Morphology – Growth can be in a follicular, follicular and diffuse, or diffuse pattern; when a follicular pattern is present, the follicles are ill-defined. (See 'Morphology' above.)

•Immunophenotype – The malignant cells express pan-B cell antigens (CD19, CD20, CD79a) and are always CD5 negative. Most cases express BCL6 but do not express BCL2, and staining for Ki-67 is variable. (See 'Immunophenotype' above.)

•Genetics – There is no typical or characteristic cytogenetic abnormality. (See 'Genetics' above.)

●Staging – Staging by clinical evaluation and positron emission tomography (PET)/CT is according to the TNM (tumor, node, metastases) staging system for primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome (table 1). (See 'Staging' above.)

●Diagnosis – PCFCL should be suspected in individuals with firm solitary or grouped skin lesions on the head, neck, trunk, or other sites.

Diagnosis is based on morphology and immunophenotype (table 2) of an epidermis-sparing B cell infiltrate of centrocytes and centroblasts with a follicular or diffuse pattern, and exclusion of extracutaneous disease. (See 'Diagnosis' above.)

●Differential diagnosis – PCFCL is distinguished from reactive processes, other primary cutaneous B cell and T cell lymphomas, and systemic lymphomas by morphology, immunohistochemistry, and exclusion of extracutaneous involvement. (See 'Differential diagnosis' above.)

●Management – Management is informed by symptoms and the number/distribution of cutaneous lesions.

•Solitary/localized – For symptomatic solitary lesion(s) that can be contained in one radiation therapy (RT) field, we suggest RT rather than observation, surgical excision, or systemic therapy (algorithm 1) (Grade 2C). (See 'Solitary or localized lesions' above.)

Typical treatment is 20 to 24 gray (Gy) RT with ≥1 to 1.5 cm margin of uninvolved skin, but lower doses may be acceptable. For patients who decline RT, topical or intralesional steroids, observation, or surgical excision are acceptable.

•Multiple or scattered lesions – For lesions that do not fit in one RT field, we suggest RT for the most symptomatic lesions rather than multiple surgeries, rituximab, or multiagent chemotherapy (algorithm 1) (Grade 2C). (See 'Multiple sites or scattered lesions' above.)

We generally limit RT to ≤3 sites, but low-dose RT (2 Gy x 2) can be given if additional symptomatic skin lesions develop.

•Extensive/diffuse disease – For extensive or diffuse symptomatic disease, we suggest single-agent rituximab rather than observation, RT, or multiagent chemotherapy (algorithm 1) (Grade 2C). (See 'Extensive or diffuse disease' above.)

●Relapse – Approximately one-third of patients relapse after initial RT. Most relapses are confined to the skin and are treated with the same modalities as initial therapy. (See 'Relapse' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Arnold S Freedman, MD, who contributed to earlier versions of this topic review.